RARE DISEASE
Large granular lymphocyte leukemia
Large granular lymphocyte leukemia
Large granular lymphocyte leukemia
Drug discovery
2
drugs
With orphan designations
Overview
Large granular lymphocyte leukemia (LGLL) is a rare chronic lymphoproliferative disorder of cytotoxic T or NK cells, characterized by clonal expansion of large granular lymphocytes (>6 months), cytopenias (neutropenia, anemia), and autoimmune associations like rheumatoid arthritis. Diagnosis requires peripheral blood analysis, flow cytometry (CD3±/CD8+/CD57+), and T-cell receptor clonality testing. Management relies on immunosuppressive therapy, with indolent progression but morbidity linked to infections and transfusion dependence [1][2][6][14].
Burden
Median survival: ~9 years (reduced vs general population), with mortality driven by infections from neutropenia [2][11][15]
Chronic management: 45% require systemic therapy at diagnosis; frequent relapses necessitate long-term immunosuppression [2][6][12]
Economic impact: Costs from recurrent hospitalizations, transfusions, and biologic therapies for cytopenias/autoimmunity [9][14]
Therapies
First-line: Methotrexate (10 mg/m² weekly) for neutropenia; cyclophosphamide (50-100 mg/day) or cyclosporine (3 mg/kg/day) for anemia [3][6][12][16]
Refractory disease: Purine analogs (fludarabine), alemtuzumab, or splenectomy [6][12][18]
Supportive care: G-CSF for severe neutropenia; indefinite maintenance therapy often required [8][16]
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
309 drug discovery papers about Large granular lymphocyte leukemia, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
309 drug discovery papers about Large granular lymphocyte leukemia, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-06 | Multilineage lymphoid clonal hematopoiesis: a cross-sectional, correlative analysis of plasma cell dyscrasias and large granular lymphocytic leukemia.
Clonal expansions in large granular lymphocytic leukemia (LGLL) may arise in response to immune dysregulation in the context of other hematologic malignancies. This study aimed to investigate the co-occurrence of LGLL and plasma cell dyscrasias (PCDs) to assess its prevalence, features, and potential underlying mechanisms. We conducted a cross-sectional study involving 2064 PCD cases and 534 LGLL cases. Of the 534 LGLL cases, 20% co-occurred with PCD, while LGLL was present in 2% of the 2064 PCD cases. Among 117 patients with both conditions, PCDs were predominantly associated with IgM M-protein, while LGLL patients had increased NK-cell proliferation and fewer mutations in STAT3/5B. The co-occurrence was linked to a higher incidence of autoimmune conditions, B-cell neoplasms, and more severe immune-mediated cytopenias. In symptomatic PCD/LGLL patients with low plasma-cell infiltration, B-cell-targeted therapies outperformed immunosuppression, suggesting humoral involvement. Correlation with biological parameters revealed elevated interleukin-6 and inhibitory effects of sera of symptomatic PCD/LGLL patients on hematopoietic cells. Our findings suggest an association between PCD and LGLL, characterized by distinct features that may have significant implications for clinical management. These results highlight the importance of considering hematologic co-occurrences in clinical practice and warrant further investigation into the molecular mechanisms linking these conditions.
2026-07-28 | Clinical Manifestations and Genetic Profile of Chinese Patients with NK-Cell Large Granular Lymphocytic Leukemia-A Single-Center Retrospective Analysis.
Natural killer cell large granular lymphocytic leukemia (NK-LGLL) is a rare and heterogenous lymphoproliferative disorder. This study retrospectively evaluated 35 consecutive Chinese patients (median age 58 years) to evaluate their unique clinical-biological profiles and treatment responses. Our Chinese population exhibited a distinct comorbidity spectrum, characterized by a lower prevalence of concurrent arthritis (2.9%) and secondary malignancies, compared with Western cohorts. At diagnosis, 31.4% of the cohort had neutropenia, 42.9% had anemia, and 31.4% had thrombocytopenia. The median large granular lymphocyte count was 3.9 × 109/L (range 0.11-114.8 × 109/L; IQR 1.9 × 109/L, 5.9 × 109/L). Immunophenotyping consistently identified as a CD3- CD56+ clone. Notably, genomic profiling via NGS revealed a STAT3 mutation rate of 14.3%. Regarding therapeutic efficacy, frontline immunosuppressive therapy with cyclophosphamide or cyclosporine was associated with favorable clinical responses (best overall response, complete remission rate 66.7% for both). Additionally, sirolimus emerged as a potentially highly effective salvage option, yielding an overall response rate of 85.7% (95%CI 42.1-99.6%) and complete remission rate of 57.1%. With an estimated 3-year overall survival rate of 85.6% (95%CI 73.3%, 99.8%), our findings suggest a generally indolent clinical course of NK-LGLL in this Chinese cohort and highlight the potential of mTOR inhibition in refractory cases, warranting further prospective investigation.
2026-07-23 | [Sustained complete remission achieved with tofacitinib in a refractory T-cell large granular lymphocytic leukemia].
Treatment of large granular lymphocytic leukemia, particularly T-cell leukemia (LGL-T), remains challenging. JAK inhibitors, although still scarcely evaluated, appear promising. An 85-year-old woman was treated for a refractory LGL-T associated with neutropenia, unclassified polyarthritis and vitiligo. During the 7-year course of the disease, she received alternatively cyclosporine, cyclophosphamide and methotrexate, associated with prednisone and/or filgrastim. During a severe relapse with agranulocytosis complicated by infectious pneumonia, no response was observed after 14 days of filgrastim. Ten days after initiation of tofacitinib, a marked increase of the neutrophil count (98G/L) occurred, associated with Sweet syndrome. Both resolved rapidly with filgrastim discontinuation. Tofacitinib allowed a rapid and complete remission of both hematological and clinical manifestations, which was maintained throughout 37 months of follow-up. This report adds to the limited evidence supporting tofacitinib in LGL-T and further highlights the potential of JAK-inhibition, particularly in refractory and systemic forms.
2026-06-23 | Auer Rod-Like Inclusions in T-cell Large Granular Lymphocytic Leukaemia.
A 71-year-old man presented with cytopenias and splenomegaly. Diagnostic workup revealed T-cell large granular lymphocytic leukemia (T-LGLL), characterized by a clonal CD8+ T-cell population with STAT3 mutation. A rare morphological finding of myeloperoxidase-negative Auer rod-like inclusions in the leukemic lymphocytes was observed, a feature seldom reported in this T-cell malignancy.
2026-06-17 | Observation of Hematologic Improvement with Luspatercept in Patients with Anemia from Diverse Hematologic Disorders: A Single-Center Retrospective Clinical Analysis
Background: Anemia is a common clinical condition in hematology, associated with diverse etiologies and treatment strategies, many of which have notable limitations. Luspatercept, a novel erythroid maturation agent, has shown promise in treating anemia, particularly in patients with β-thalassemia and myelodysplastic syndromes (MDS). This study aimed to evaluate the real-world hematologic effectiveness of luspatercept across various anemia subtypes. Materials and Methods: A retrospective observational study was conducted on 22 patients with anemia of different origins—MDS, post-hematopoietic stem cell transplantation (HSCT), aplastic anemia (AA), and T-cell large granular lymphocytic leukemia (T-LGLL)—who received luspatercept therapy at the 960th Hospital from June 2023 to January 2025. Hematologic improvement was assessed using the International Working Group (IWG) 2018 criteria for erythroid response (HI-E). Pre- and post-treatment changes in hemoglobin (Hb), reticulocyte percentage (RET %), and absolute reticulocyte count (RET #) were analyzed using the Wilcoxon Signed-Rank Test. Multivariate regression was employed to control for age, gender, and disease severity. Statistical significance was set at P ≤ 0.05, and all analyses were performed using SPSS version 27.0. Results: Among the 22 patients, 10 (45.5%) had MDS (5 low-risk, 5 intermediate-to-high-risk), 6 (27.3%) post-HSCT anemia, 4 (18.2%) AA, and 2 (9%) T-LGLL. A total of 16 patients (72.7%) achieved a clinically meaningful erythroid response. Seven (43.8%) of these remained transfusion-independent until the last follow-up, with a median duration of 19.5 weeks (range: 8.6–47). Median time to initial response was 3.86 weeks (range: 0.57–25.57). Significant increases were observed in Hb (P < 0.001) and RET # (P = 0.001), while the increase in RET % did not reach statistical significance (P = 0.088). These findings support the efficacy of luspatercept in promoting erythropoiesis and improving anemia in a heterogeneous patient population. Conclusion: Luspatercept demonstrated significant hematologic improvement, particularly in hemoglobin levels, in patients with anemia from various hematologic disorders. These results support its broader therapeutic potential. Future multicenter, prospective studies are warranted to validate its role in treating other forms of anemia.
2026-08-06 | Multilineage lymphoid clonal hematopoiesis: a cross-sectional, correlative analysis of plasma cell dyscrasias and large granular lymphocytic leukemia.
Clonal expansions in large granular lymphocytic leukemia (LGLL) may arise in response to immune dysregulation in the context of other hematologic malignancies. This study aimed to investigate the co-occurrence of LGLL and plasma cell dyscrasias (PCDs) to assess its prevalence, features, and potential underlying mechanisms. We conducted a cross-sectional study involving 2064 PCD cases and 534 LGLL cases. Of the 534 LGLL cases, 20% co-occurred with PCD, while LGLL was present in 2% of the 2064 PCD cases. Among 117 patients with both conditions, PCDs were predominantly associated with IgM M-protein, while LGLL patients had increased NK-cell proliferation and fewer mutations in STAT3/5B. The co-occurrence was linked to a higher incidence of autoimmune conditions, B-cell neoplasms, and more severe immune-mediated cytopenias. In symptomatic PCD/LGLL patients with low plasma-cell infiltration, B-cell-targeted therapies outperformed immunosuppression, suggesting humoral involvement. Correlation with biological parameters revealed elevated interleukin-6 and inhibitory effects of sera of symptomatic PCD/LGLL patients on hematopoietic cells. Our findings suggest an association between PCD and LGLL, characterized by distinct features that may have significant implications for clinical management. These results highlight the importance of considering hematologic co-occurrences in clinical practice and warrant further investigation into the molecular mechanisms linking these conditions.
2026-07-28 | Clinical Manifestations and Genetic Profile of Chinese Patients with NK-Cell Large Granular Lymphocytic Leukemia-A Single-Center Retrospective Analysis.
Natural killer cell large granular lymphocytic leukemia (NK-LGLL) is a rare and heterogenous lymphoproliferative disorder. This study retrospectively evaluated 35 consecutive Chinese patients (median age 58 years) to evaluate their unique clinical-biological profiles and treatment responses. Our Chinese population exhibited a distinct comorbidity spectrum, characterized by a lower prevalence of concurrent arthritis (2.9%) and secondary malignancies, compared with Western cohorts. At diagnosis, 31.4% of the cohort had neutropenia, 42.9% had anemia, and 31.4% had thrombocytopenia. The median large granular lymphocyte count was 3.9 × 109/L (range 0.11-114.8 × 109/L; IQR 1.9 × 109/L, 5.9 × 109/L). Immunophenotyping consistently identified as a CD3- CD56+ clone. Notably, genomic profiling via NGS revealed a STAT3 mutation rate of 14.3%. Regarding therapeutic efficacy, frontline immunosuppressive therapy with cyclophosphamide or cyclosporine was associated with favorable clinical responses (best overall response, complete remission rate 66.7% for both). Additionally, sirolimus emerged as a potentially highly effective salvage option, yielding an overall response rate of 85.7% (95%CI 42.1-99.6%) and complete remission rate of 57.1%. With an estimated 3-year overall survival rate of 85.6% (95%CI 73.3%, 99.8%), our findings suggest a generally indolent clinical course of NK-LGLL in this Chinese cohort and highlight the potential of mTOR inhibition in refractory cases, warranting further prospective investigation.
2026-07-23 | [Sustained complete remission achieved with tofacitinib in a refractory T-cell large granular lymphocytic leukemia].
Treatment of large granular lymphocytic leukemia, particularly T-cell leukemia (LGL-T), remains challenging. JAK inhibitors, although still scarcely evaluated, appear promising. An 85-year-old woman was treated for a refractory LGL-T associated with neutropenia, unclassified polyarthritis and vitiligo. During the 7-year course of the disease, she received alternatively cyclosporine, cyclophosphamide and methotrexate, associated with prednisone and/or filgrastim. During a severe relapse with agranulocytosis complicated by infectious pneumonia, no response was observed after 14 days of filgrastim. Ten days after initiation of tofacitinib, a marked increase of the neutrophil count (98G/L) occurred, associated with Sweet syndrome. Both resolved rapidly with filgrastim discontinuation. Tofacitinib allowed a rapid and complete remission of both hematological and clinical manifestations, which was maintained throughout 37 months of follow-up. This report adds to the limited evidence supporting tofacitinib in LGL-T and further highlights the potential of JAK-inhibition, particularly in refractory and systemic forms.
2026-06-23 | Auer Rod-Like Inclusions in T-cell Large Granular Lymphocytic Leukaemia.
A 71-year-old man presented with cytopenias and splenomegaly. Diagnostic workup revealed T-cell large granular lymphocytic leukemia (T-LGLL), characterized by a clonal CD8+ T-cell population with STAT3 mutation. A rare morphological finding of myeloperoxidase-negative Auer rod-like inclusions in the leukemic lymphocytes was observed, a feature seldom reported in this T-cell malignancy.
2026-06-17 | Observation of Hematologic Improvement with Luspatercept in Patients with Anemia from Diverse Hematologic Disorders: A Single-Center Retrospective Clinical Analysis
Background: Anemia is a common clinical condition in hematology, associated with diverse etiologies and treatment strategies, many of which have notable limitations. Luspatercept, a novel erythroid maturation agent, has shown promise in treating anemia, particularly in patients with β-thalassemia and myelodysplastic syndromes (MDS). This study aimed to evaluate the real-world hematologic effectiveness of luspatercept across various anemia subtypes. Materials and Methods: A retrospective observational study was conducted on 22 patients with anemia of different origins—MDS, post-hematopoietic stem cell transplantation (HSCT), aplastic anemia (AA), and T-cell large granular lymphocytic leukemia (T-LGLL)—who received luspatercept therapy at the 960th Hospital from June 2023 to January 2025. Hematologic improvement was assessed using the International Working Group (IWG) 2018 criteria for erythroid response (HI-E). Pre- and post-treatment changes in hemoglobin (Hb), reticulocyte percentage (RET %), and absolute reticulocyte count (RET #) were analyzed using the Wilcoxon Signed-Rank Test. Multivariate regression was employed to control for age, gender, and disease severity. Statistical significance was set at P ≤ 0.05, and all analyses were performed using SPSS version 27.0. Results: Among the 22 patients, 10 (45.5%) had MDS (5 low-risk, 5 intermediate-to-high-risk), 6 (27.3%) post-HSCT anemia, 4 (18.2%) AA, and 2 (9%) T-LGLL. A total of 16 patients (72.7%) achieved a clinically meaningful erythroid response. Seven (43.8%) of these remained transfusion-independent until the last follow-up, with a median duration of 19.5 weeks (range: 8.6–47). Median time to initial response was 3.86 weeks (range: 0.57–25.57). Significant increases were observed in Hb (P < 0.001) and RET # (P = 0.001), while the increase in RET % did not reach statistical significance (P = 0.088). These findings support the efficacy of luspatercept in promoting erythropoiesis and improving anemia in a heterogeneous patient population. Conclusion: Luspatercept demonstrated significant hematologic improvement, particularly in hemoglobin levels, in patients with anemia from various hematologic disorders. These results support its broader therapeutic potential. Future multicenter, prospective studies are warranted to validate its role in treating other forms of anemia.
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Drug Discovery Landscape
2 orphan drug designations for Large granular lymphocyte leukemia.
2 orphan drug designations for Large granular lymphocyte leukemia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Dibotatug | antibodies | EMA | 2026-03-25 | — | FGK Representative Service GmbH |
human anti-CD94 IgG1 monoclonal antibody (non-fucosylated) | antibodies | FDA | 2023-03-23 | — | Dren Bio, Inc |
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